Certain amino alcohols and ketones



Patented Dec. 1, 1953 UNITED STATES PATENT OFFICE CERTAIN AMINO ALCOHOLS AND KETONES Darmstadt, Germany No Drawing. Application March 2, 1,953, SorialNo. 339,924

15 Claims. ,1

This invention relates to new and useful improvements in certain amino alcohols and ketones and is a continuation-in-part of our co-pending applications Serial No.:.86,l23- filedApril 7, 1949, now abandoned, and Serial No. 299,494 filed July 17, 1952.

One of the objects of the invention comprises among others a new and useful amino alcohol product having valuable therapeutic and pharmacological properties.

Another object of v the invention-comprises a novel mode of producing the-amino alcohols in accordance with the invention.

A further objectof the-invention comprises valuable amino ketones::which lend themselves readily to the preparation of the novelamino alcohols in accordance with the invention.

A still further object of the invention comprises a novel mode preparing such amino-ketones'.

The foregoing and still further objectsof the invention will be apparent from the following description:

The novel compounds in accordance "with the invention possess remarkable therapeutically v-alin which 13.. represents an aliphatichydrocarbon radical of from 2-5 carbon atoms, inwhichX is a member of. the ,groupi.of radicals consisting t -CO- and CHOH.-. ,.in which R is. a member of the group consisting. of hydrogen anda phenyl methyl radicalin which? is .a-member of the o upon d astolicbloodpressurewhile theketo compounds. in accordance with the invention. have proven valuable th relief ortreatm nt of asthmatic conditions. remarkable .aspect of the novel productsjn accordance withthe invention and particularly .the alkanol. products, is

the fact that otherwise similar. products for h howev ninis less than 2,- i. c. .ai-m thyl radical how on y .airaction of the eff cti ene s of. our n el p ducts forwhich ,R. is an aliphatic i a radical of from -2- 5 carbon atoms.

The novel alkanol products within one embodi- 2 ment of the invention constitute l-(p-hydroxyphenyl) -l-hydroxy-2-(aralkylamino) propanes of the general formula inwhich-R represents any substantially aliphatic hydrocarbon radical offrom 2-5- carbon atoms-of either straight .or branched chain configuration and preferablyof the lattertype w-ith lthe NH grouping. in C linkage with an intermediate carbon atom of the radical, andby-way. of-further preference, in linkage with. a C atom at which chain branching occursand in which Y is either the methyl or ethyl radical.

Within the prcferredlembodiment of the products in accordancewith the-invention 'R is, for

instance, representediiby anethyl, propyL-i-sopropyl, .butyl, iso'buty-l, .pentyl, isopentyl, or simiin which Y represents a methyl orethyl radical and in which R represents hydrogen or any other hydrogen substitutable or convertible radical and preferably a phenyl methyl radical which will permit to be split oil by hydrogenation in the presence of a catalyst to convert the B o -radical into an OH radical.

. h ab ve r f rred-to hetonep u ts may be converted to thedesired amino alcohol product in accordance with the invention by reducing the tone toa hy oxy ou and suitable splittin oil the radical, in the .p;-hydroxy,position .to convert the same to a ;fr;e e OH-group. -';lhe latter ma be a o p ished-in arious w rem which are substantiallyconventional and known to h a tisan, m r-includ s n fi ation .or other ester splitting reaction, heating with mineral acids, alkali hydroxides; or carbonates, etc. The ketone group may be convertedto a hyd y r p n ord nc zwith co vent ona practices but preferably by way of reduction with hydrogen in the presence of a catalyst. Within sal a 3 the scope of the preferred procedure of the invention it is possible to combine the splitting ofi the H-substituted radical of the hydroxy grouping by hydrogenation in the presence of a catalyst while simultaneously reducing the CO grouping to a CHOH group. If a product of the Schiffs base type is used, the -N=R group may be converted to an NH-R, group in accordance with conventional methods, though we prefer such conversion by way of a reduction with hydrogen in the prasence of a hydrogenation catalyst and it may then be of advantage to simultaneously obtain conversion of the N: group to NH and the CO group to -CI-IOI-I- and preferably while simultaneously splitting off the radical to convert the -OR group to OI-I.

The novel ketones of the above mentioned general formula (II) may be, for instance, prepared by suitable condensation of a halogeno-p-hy-.

ether groupings are preferably those of alcohol radicals which may be split ofi by hydrogenation, as herein set forth. Suitable aralkyl amines may (p) HO-'CsH4--CO-CO-CH3 VII (or the corresponding butane dione as the case may be) with a suitable aralkyl amine of the 7 type having 2-5 carbon atoms in either straight be, for example, aor B-phenylethylamine or condensation agents may be used to expedite or catalyze the reaction.

A suitable hydroxy vpropio phenone condensation with a aralkylamine of the type useful for the preparation of products in accordance with the invention (2-5 carbon atoms in the aliphatic chain) is, for instance, examplified by the smooth reaction of equi-molecular amounts in the absence of solvents of for instance p-benzyloxy-abromo-propio-phenone (III) with 1-phenyl-3- amino-butane (IV) resulting in the formation of (1 methyl-2-p-benzyloxy-phenyl-2-oxo-ethyl) (1'-methyl-3-phenylpropyl) -amine (V) in accordance with the following equations:

CH3 CH3 (III) V) CH3 CH3 The Schiffs base of the general Formula Ila above may be converted by suitable reduction or hydroge'nationto' its amino hydroxy compound of the general formula (p) R O-OsH CHOH?HNHRC0H5 Y VI in which R and Y are as above-stated.

This product may then be treated for the splitting off of the R group in the manner herein stated.

It is generally desirable in most of these condensation reactions of the type herein referred to if the hydroxy group is suitably protected such as by etherification or esterification thus resulting in ether or ester products from which it is necessary to split off the acid or alcohol radicals as the case may be in order to obtain the free hydroxy compounds in accordance with the invention.

A suitable Schiffs base as herein referred to or branched chain configuration. The resulting product is a Schiffs base or aldehyde ammonia forming an intermediate product in which the ketone and =N- groups may be reduced to form a hydroxy amine of the general Formula VI above set forth. It is also possible, in accordance with the invention,.to conduct the reduction of the Schiffs base ina manner to simultaneously split off the ester or ether radical to thereby convert '"the base directly to the desired hydroxy amine Y VIII (in which R and Y are as above set forth) with an aralkyl or aralkylene ketone or aldehyde such as, for instance, acetophenone, benzylacetone, benzalacetone or phenylacetaldehyde and hydrocinnamic aldehyde. The resulting products also contain a -C=N- grouping which may be reduced as, for instance, by hydrogenation. Such hydrogenation may be carried out to either successively reduce the =N- group (together with alkylene group, if any) and the phenyl ester or ether grouping or the hydrogenation may be conducted in accordance with the invention to simultaneously obtain the splitting off of the ester or ether radical to result in the formation of the free phenyl hydroxy group.

Suitable aralkanolamines of the type for instance exemplified by Formula VIII may be prepared for instance from a suitable ester or ether of a p-hydroxy-propio or butyro phenone. The latter may be converted with nitrous acid or esters thereof into the isonitroso compounds, which are then reduced. The reduction may be accomplished in successive stages or ina manner to simultaneously split off the ester or ether radical as, for instance, by catalytic hydrogenation with palladium. It is also possible to split off the ester or ether radical during or after the condensation of the aralkanolamines with the aralkyl ketone or aldehyde so that it is only necessary to reduce the resulting product for the conversion of the =N- group.

Alternatively, it is possible to produce aralkanolamines with a free unsubstituted phenyl hydroxy group such as by catalytic hydrogenation of p-hydroxy-a-amino-propiophenone or phydroxy-p-amino butyrophenone, as the case may be, preferably in aqueous suspension at normal temperature in either th presence of palladium catalyst atatmospheric pressure or a pressure slightly in excess of atmospheric or in the pres- .ence of nickel catalyst, such as Raney nickel and preferably at high pressure.

Byway of still further preferre embodiment of the invention, the novel alkanol compounds may be produced by hydrogenation of l-(p-hydroxyphenyl) -2-amino-propanone- 1) (or corresponding butanone product) in organic solvents in which the same is relatively sparingly soluble,

racists C I-IR' :CO;R" IXa .in which Rf represents an aliphatic hydrocar- ..bon radical, .R "".ahydrogen atom of aliphatic hydrocarbon radical and-in whichthe sum of the carbonatomsofRfl and R"" is 1-4.

ZIhisreaction and the smooth production of the compounds in. accordance with th invention in this manner is surprising, inthat it should be normally expected under the conditions under which the 0. amino 'ketone' isto be reacted with the aldehyde or rketone, that .it would combine with itself; with the formation 015a double-internal aldehyde ammonia compound and the subsequent splitting olf of water toform a dihydropymzine which in turn wouldbeconverted' into a stable pyra'zine by loss'of two'hydrogen atoms. "The 'normally expected reaction resulting in'the "ultimate formation of pyrazine does not take "place-however, in the special'case of I-(p-hydroxyphenyl) -2-amino-propanone- 1) (or correspondingbutanone product) whichreacts with "excellent yields to form the novel'compounds in accordance with the invention by its catalytic hy- "drogenation' inthe presence 'of' a ketone or alde- "hyde' ('under'Formula IX). The reaction is exemplified forthe propanone "by the following equation:

(1)) no-oun-w o--onTNH2, R"C O"R-CaHa to Inprder tocarry out the reaction the aminoketone, which has been prepared in the usual :mannendor example, by reacting acetoxy-av bromo+propiophenone (or corresponding butyro phenone) with' aqueou ammonia, is suspended "inorganic solvents inwhich it is' sparingly soliuble, the ketone or 1 aldehyde is added in equimolecular proportionsor in slight excess with respect-to the aminor-k'etone, and the mixture is shaken in contact with hydrogen'in th presence of :a hydrogenation catalyst at atmospheric-pressure or under'increased pressure.

The. ketones employed -may, for example, be

iacetophenone, i'benzalac'etoneor -'benzylacetone and thefialdehydesemployed may, for example, belcinnamicaldehyde. orhy drocinnamic aldehyde. The -solvents chosen are-those which are partially lmiscible-with water I and contain no carbonyl -group. ltsis particularly advantageous to use-1 lowerralcohols. Methanol is preferably used but ethylalcohol or isopropylalcohol can also be used. -Thealcohols may beused in the anhydrous condition, but alcohols containing-water may also he used; for example, 80 methanol.

I Suitable hydrogenation catalysts are Raney :nickel-ornoble'imetal catalysts, such as palladiu'm hydroxide. or ba'rium sulphate or platinum -black, preferably platinum oxide. Two mols of hydrogen are taken 1 up L in the hydrogenation. :1

- The .aminoketone forming the starting material goesinto solution andthe desired compound of vthe general Formula I is produced in good yield. If the aldehyde or ketone employed'contains readily hydrogenated doublebonds in the residue -:i

Rf, then the latter are saturated and a-corre- "spondingly fgreater, quantity of hydrogen is taken up.

: Thewreaction: solutions are'worked up in conruentional-Lmanner; Since theiend product ofther yp palladium. The products subjected to hydrogengeneral Formula. IXa contains 3,,a'syminetric'car the formation of 4 stereoisomeric racemates-is possible.

Wherever hydrogenation is to be eifectuated in conjunction with the preparation of any of the products or intermediary products 'herein referred to, such hydrogenation is advantageous- 1y carried out in the presence of suitable catalysts and preferably catalysts .oi the noble metal Especially good results are obtained using ation in the presence. of noble metal catalysts are preferably the salts, thereby resulting in the formation of the correspondingsalts of the desired compounds in'accordance with the invention of the general Formula I.

When using nickelcatalysts for hydrogenation purposes in accordance with the invention, and especially the lesser expensive nickel catalysts of, for instance, the Raney nickel type, the same selectively catalyze the hydrogenation reaction of the salts 'of the amino ketones'ofthe general Formula II in a manner to'ismoothly split off the etherifying alcohol radical of the phenyl or phenyl methyl type without reducing the-ketone group thus resulting in'theformation of a phenol ketone having-a free hydroxy group, i. e. a product of the general Formula II in whicht-R-'-==H. Thus, for instance, when subjecting-.thehyd-ro- .bromide 01 the benzyl ether'of an amino .ketone 35 product of the general Formula II to hydrogenation in the presence of Raney nickel, the benzyl residue is readily split oil. The reaction gives substantially quantitative yields of the amino ketone phenols.

In order to then produce from these latter products the aminorhydroxy compoundsgenerally corresponding to Formula I, hydrogenation may be continuedwithpalladium as catalyst i of the general Formulal by catalyticaliy hydrogenating the amino ketones .or theircorrespond- .ingischiffs base in the form of their salts in a substantially one step-procedure using noble metal catalysts, the two step process may-be used where special circumstances and conditions may .at times make it desirable to produce the inter- I mediaryamino ketone phenols.

Within the preferred procedure of our invention, however, a substantially one step hydrogenation of .the-aminoketone others of the benzyl ether type to the desired amino hydroxy phenols maybe carriedout Without the necessity of using .a relatively costly catalyst such as of the noble metal type.

.This result may be accomplished by hydrogenating the free amino ketone ether of the general Formula II in the form of the free base -..preferably a catalyst of Raney nickel. The hythereof in the presence of a' nickel catalystand -uctszand to .treat thesame' with one equivalent of alkali per mol. of the .salttobe hydrogenated inicthe. formof an alkali ametal hydroxide ori i-ts corresponding --aleoholate.- Alternatively, the

7 free bases as such may be used as they may have been obtained in any conventional manner .including alkalinization of their salts and solvent extraction of the free base or by way of any method including those herein specified in which the .free base as such is produced.

Whenever the two step manner of hydrogenating the amino ketones of the general Formula II :is used, it is possible to conduct the second hydrogenation step, i. e. the hydrogenation of the intermediate amino ketone phenol, by the conversion of the salt thereof to the free base and proceeding with the hydrogenation of the latter in the presence of a nickel catalyst. Thus, when proceeding in the two step manner, the amino ketone, as exemplified by Formula II, is first hydrogenated in the form of its salt in the presence of a nickel catalyst, and hydrogenation is thereafter conducted in the presence of nickel catalyst in the form of the base of the intermediary product, which may be accomplished by adding 2. mol equivalent of a caustic alkali after the completion of the first hydrogenation step and then continuing the hydrogenation,

The following examples are furnished by way of illustration and not of limitation:

EXAMPLE I Preparation of l-(p-hydroxyphenyl) 2- ('yphenyl-propylamino) -propanol- (1 5 grams of the hydrobromide of l-(p-hydroxyphenyl) 2 ('y phenylpropylamino)propanone-(l) of melting point 174 C. were shaken in contact with hydrogen with 0.2 gram of platinum oxide in 100 cos. of methanol. The hydrogenation stopped when 1 mol of hydrogen had been taken up. The solution was filtered from the catalyst, the methanol was evaporated and the residue was crystallized from alcohol with the addition of a little ether. The hydrobromide of the compound named in the example heading was obtained with a melting point of 174 C. It showed a marked melting point depression when melted with the starting material, which happens to melt at the same temperature.

The starting material is prepared as follows: p-benzoxy-a-bromo-propiophenone is prepared by benzylating p-hydroxypropiophenone with benzyl chloride and potassium carbonate in methanol and subsequent bromination. The product is then heated for one hour with 1 mol phenyl-propyl-amine to 80 C. to form the hydrobromide of l-(p-benzoxy phenyl) 2- (7- phenylpropylamino) -propanone-(1) of melting point 209-210 C. The latter is decomposed into toluene and the hydrobromide of l-(p-hydroxyphenyl) 2-('y phenylpropylamino) propanone- (l) by shaking in contact with hydrogen with a not too active palladium catalyst, for example, with palladium on barium sulphate in 90% methanol, 1 mol of hydrogen being taken up. The same compounds can also be obtained by heating p hydroXy-phenyl-a-bromo-propiophenone, obtained as described by Auwers and N011, Liebigs Annalen 535, p. 247 (1938) dissolved in benzene with -phenylpropylamine for an hour on the Water bath.

EXAMPLE II Preparation of I-(p-hydrozryphenyl)-2-(a-methyl- -phenyl-propylamino) -propanl- (1) grams of the hydrobromide of l-(p-hydroxyphenyl) 2 (a-methylw-phenyl-propylamino)- propanone-(l), of melting point 141 C. (crystallized from water) were shaken in 150 ccs, methanolwithl-figrams of a 10% palladiumhydroX- ide barium sulphate catalyst in contact with hydrogen. The hydrogenation ceased when 1 mol of hydrogen had been taken up. The solution was filtered from the catalyst and concentrated, and the hydrobromide of the compound named in the example heading was precipitated by addition of ether. It melted after recrystallization from alcohol at 214215 C. and the free base liberated therefrom at 110-112 C. The starting material was obtained in amanner analogous to that described in Example I.

EXAMPLE I11 Preparation of 1-(p-hydroxyphenyl)-2-(a.-methyl- -phenyl-propylamino) -propanol- (1 1 gram of l-(p-hydroxyphenyl)-2-(a-methyl- -phenyl-propylamino) -propanone-(l) of melting point 147-148 C. were shaken with about 0.25 gram of Raney nickel in 25 ccs. methanol in contact with hydrogen. After four hours the quantity of hydrogen calculated for 1 mol had been taken up. The solution was filtered from the catalyst, and by evaporation and recrystallization of the residue from methanol of the theoretical yield of the base specified in the example heading was obtained, having a melting point of 111-112 C. The mother liquor contained stereoisomeric compounds of the same constitution.

The starting material was obtained as described in Examples I and II and the base used as the starting material was liberated in the usual manner.

EXAMPLE IV Preparation of stereoisomeric I-(p-hydroxyphenyl) 2 (a methyl- -phenyl-propylamino) -propanol- (1) 5.5 grams of the hydrobromide of a steroisomer of the compound mentioned in Example II, l-(phydroxyphenyl) -2-(a-methyl-'y-phenyl propylamino) -propanone-(1), of melting point 201 C. (crystallized from water) were used. This product was obtained by reacting toluene sulphonic acid ester of abromo-p-hydroxy-propiophenone with l-phenyl-B-amino-butane, fractional crystallization of the hydrobromide produced and splitting 01f of the toluene sulphonic acid residue with alkali. The aforestated amount of the hydrobromide was shaken as in Example II with 2.0 grams of a 10% palladium hydroxidebarium sulphate'catalyst in 125 ccs. methanol in contact with hydrogen. The hydrobromide of the hydrogenation product was isolated in the usual manner after 1 mol of hydrogen had been taken up, and melted after recrystallization from dilute hydrobromic acid at 215-216 C. The base liberated therefrom melted at 139-140 C. and the hydrochloride melted at 223-224" C.

The same compound was obtained when, instead of the hydrobromide, the free base of melting point 1'71-172 C. was hydrogenated with Raney nickel in methanol as in Example III. By way of alternative procedure, the base was hydrogenated in aqueous medium with the ketone starting material (melting point 171-17 2 C.) dissolved in 1 mol of aqueous potassium hydroxide and shaken with Raney nickel in contact with hydrogen.

EXAMPLE V 2 grams of 1- (p-hydroxyphenyl) -2-(' -phen 1 propylamino)-propanol-(1), substituted at the Q phenolic hydroxyl by a p-toluenesulphonyl residue, were heated for 3- hours on the water bath with an excess 10% alcoholic caustic potash so-.

lution, until the solution was no longer rendered turbid (by unchanged base) on addition of water; Theaqueous medium was then worked up in the usualmanner, to form an ethereal solution of the base specified in the example heading. The hydrobromide of melting point 174 C. was obtained from this base solution by addition of ethereal or aqueous hydrobromic acid. Any other salt may be obtained from the ether solution of the base by adding another acid of the type known to formsalts with -NH-- groups.

The starting material can be obtained by brominating the p-toluene sulphonic acid ester of, p-hydroxypropiophenone, melting at '78 0. (Which may be obtained from p-toluen sulphenol chloride and p-hydroxypropiophenone in pyridine as described by Sekera and. Marvel, Journ. Amer. Chem. Soc. 55, p. 345, (1933)) to form the a-bromo compound melting at 75 0., reacting this with p-phenylpropylamine and reducing the ketone group.

EXAMPLE VI Preparation of 1- (p-hydromyphenyl) 2- (l -methyL-v-phenyZ-prop1/Zdmine) -p1opanoZ- (1 9.3. grams of the compound specified in the ex ample. heading, but substituted at the phenolic hydroxyl by the toluene sulphonyl residue, were saponified as in Example V with 50 cos. of 10% alcoholic caustic soda. The base specified in the heading, of melting point 111412 C.', was ob tained by working up in the usual manner. The hydrochloride melts at 222-224 C. and at 205 206." C. when it contains 1 molecule of water of crystallization.

The starting material was obtained by reacting the toluene sulphonic acid ester of a-blOlIlO-D- hydr-oxypropiophenone, mentioned in Example V, in benzene with l-phenyl-aminoebutane, converting th precipitated hydrobromide. of, melting point 217-220 C. (after crystallization from methanol) into the free base melting at IO-71 C. and reducing the ketone group with aluminum isopropyl'ate by the Meerwein-Ponndorf' method, the-toluene sulphonyl residue surprisingly not being split off. By working up in the usual-manner the hydrochloride of 1-(p-hydrox'ypheny'l)-2-(amethyl-y-phenyl-propylamino) propanol (l), substituted at the phenolic hydroxyl by theptoluen sulphonyl residue, was obtained and melted at 228230 c; It gives with alkali the fre base of melting point 135l36 C. which isthen saponified.

EXAMPLE, VII

Preparation 0 j 1- (p-hydrorcyphenyl) -2- (u.-m-eth;- yz- -phenyZ-propyZwmmo) -prop1anol (1 2.8 grams of the benzyl ether ofthe compound specified in theexample heading,1of'melting point 135-136 C. (crystallized from methanol), were shaken with 1.0 gram of a palladium hydroxide barium sulphate catalyst, ina mixture of equal parts of methanol and ethanol in contact with hydrogen. The benzyl residuewas split ofi" from the phenolic hydroxyl group to form toluene within 30 minutes, 1 mol of hydrogen being taken up. The base specified inthe example heading, which melts at 110112 C., was obtained byworking up in the usual manner.

The benzyl other required as starting material wasaobtained by brominating' th benzyl'ether of p-hydroxypropiophenone, reacting the a-bromo' compound with 1 mol of l-phenol3"aminobutane, preferably in the; absence of solvents, and either hydrogenating the hydrobromide in the offvery pure methanol and shakenwith 6.0 grams of a 10% palladium. hydroxide barium sulphate.

catalyst in contactwith. hydrogen. After rather more than 2' mols of hydrogen had been taken up,

the; hydrogenation. stopped. The hydrobromide Ofthe, base, Specified ill the heading, melting at 214F215." C., was obtained in excellent yield by. filtering, off from the; catalyst, washing. with. methanol and, evaporation. 25 cos. of a freshly prepared palladium chloride solution, to which 9 grams of charcoalhas been added, may be used as the. catalyst instead of. palladium hydroxide:

The starting. material was obtained. by heating equivalent quantities of p-benzoxy-a-bromopropiophenone and 1-phenyl-3-amino -butane foran hour on the water bath in the absence of solvents; A solid crystallinecake was obtained, which was the compound used as the starting material: After being extracted with boiling; acetic acid, it-can be adjusted directly to hydrogenation. v

By reacting the corresponding" aralkylamines: instead of the phenyl amino butane herespecified' and subjecting the various resulting benzyl ethers to catalytic hydrogenation in the manner set forthqaboye, the followmg. compounds were prepared:

l-(p-hydroxyphenyl) -2'-( 8-phenyl ethylami no)'-=propanol--(l melting point of the hydro chloride 195 C: r

l- (p-hydroxyphenyl) 2"- (a-phenyl ethylami no) -propanol-('l melting point of the hydro bromide 208-209 C., of the hydrochloride 211- 212 0.,an of the base l16 C.

l-(p-hyd'roxyphenyl) -2-(a methyl-c-phenyl ethyl'amino) -propanol-(l); melting point of the hydrobromide 216 C.

l-(p-h'ydroxyphenyl) 2 -phenylpropylami no)-propanol-(1 melting point of the hydrochloride 1'78-179 C.

I-(p-hydrbxyiihenyl) -2-(o-phenyl :butylami no) -propanol:-(1)'; melting point of the hydrochloride Mil- C., and

l- (p. hydroxyphenyl) -2- (a-methyl-B-phenyl' butylami'no) -propanol'-( 1) The last. mentionedv compound was obtainedin the, form of the steroisomeric hydrochlorides, which may. be separated, by fractional crystallization. The less soluble hydrochloride melts. at 222 223C. and the more soluble melts at -186 C.

EXAlVIPLE IX Preparation of: 1:- (p-hydroxyphenyl) J w-methyl- -phenybpropylamino) -propz'mol- (1') 8 grams of" the'hydrobromide of 1- (p-benzoxy phenyl) 2.- (.a methyl -y phenyl-propylamino) propanone-(Dz, produced as described in Example VIII and; purified by twice boiling. with five.

times the quantity of acetic acid and filtration at 80? C were shaken in contact with hydrogen with 0.8 gram of Raney nickel in 70 cos. of pure methanol containing 0.96 gram (corresponding to 1 mol) of KOH. After four hours 2 mols of hydrogen had been taken up and the solution was filtered from the catalyst, evaporated in vacuo, and the residue triturated first with water to remove potassium bromide and then with methanol to remove potassium bromide. 3.7 grams (72% of the theoretical yield) of the compound specified in the heading, melting at 110- 112 C. were obtained. The remainder of the base remains in the methanol mother liquor as a mixture of stereoisomers.

When the alkali was omitted in the abovedescribed process only one mol of hydrogen was taken up rapidly, which served to split off the benzyl residue. The hydrobromide which was originally in suspension went into solution but the hydrogenation slowed down very markedly. When one equivalent of KOI-I was added to the solution, hyrogenation was immediately resumed. The yield obtained by this process was practically the same as when the alkali was added initially, and an excess of alkali may be used.

EXAMPLE X Preparation of 1-(p-hydroxyphenyl) -2-(p-phenl-ethylamino) -propanol- (1) l-(p-hydroxyphenyl) -propanedione (1.2) of melting point 85, was shaken with 1 mol of p-phenyl-ethylamine and palladium hydroxide barium sulphate catalyst in methanol in contact with hydrogen. After 2 mols of hydrogen had been taken up, the solution was worked up in the Preparation of Z-(p-hydroxyphenyl)--2-(a.-meth- .yl -phenybpropylamino) -pr0panol- (1 8.3 grams of l-(p-hydroxyphenyl) -2-aminopropanol-(l) of melting point 16l-162 C. were dissolved with 21 grams of benzyl acetone in 20 cos. of anhydrous alcohol and 5 cos. of benzene, and'the whole was heated beneath a reflux condenser (with take-off and filled with rings) for three hours on the water bath, when the greater part of the solvent distilled off. The residue was taken up in 60 cos. of pure alcohol, 0.3 gram of platinum oxide were added, and the solution shaken in contact with hydrogen. When hydrogen was no longer taken up, the solution was filtered from the catalyst, the alcohol was distilled off, the residue was taken up in methylene chloride, and the solution was shaken with dilute hydrochloric acid. Fifteen g. of a mixture of hydrochlorides crystallized out having a crude melting point of ,206-208 C.

The mixture contains two isomers of the constitution specified in the example heading, which melt respectively as free bases at ill-112 C. and 139.140 C. The two isomers are distinguished by stereoisomerism at the asymmetrical carbon atom of the aralkyl residue.

The 1- (p-hydroxyphenyl) -2-amino-propanol- (1) required as starting material may be obtained in various ways, for example, by reduction of the isonitroso compound of p-hydroxy-propiophenone. It may be obtained particularly conveniently by acetylating p hydroxy propiophenone, brominating the acetyl compound. re-

acting the a-bromo compound with concentrated aqueous ammonia, whereupon l-(p-hydroxyphenyl) 2 amino propanone (1) melting at 168l7 C. crystallizes out, and hydrogenating the latter catalytically in aqueous suspension. By evaporating the aqueous solution produced and recrystallization from alcohol, 1 (p hydroxyphenyl) -2-amino-propanol- 1) very good yield.

EXAMPLE XII Preparation of 1 (p hydroxyphenyl) 2 (aphenyZ-ethylamino) -propanol- (1 This compound was obtained as described in Example XI from l-(p-hydroxyphenyl) -2-aminopropanol-(l) and acetophenone. The hydrochloride melts at 211-212 C. (recrystallized from water).

EXAMPLE XIII Preparation of Z-(p-hydroxyphenyl)-2(a-methyl 'y phenyl propylamino) propanol (1 1.7 grams of l-(p-hydroxyphenyl)-2-aminopropanol-(l) were heated beneath a ring condenser on the water bath with 1.5 grams of benzyl acetone in 10 cos. of alcohol and 2 cos. of benzene for 3 hours and the residue was evaporated several times with ether. The residue was then dissolved in an alcohol ether mixture (1:10), amalgamated aluminum was added to the solution and the latter boiled for 18 hours under reflux, a drop of water being added from time to time in order to maintain the evolution of hydrogen. The solution was filtered hot and the hydrochloride was precipitated with hydrochloric acid. The hydrochloride melted at 213-214" C. after recrystallization from alcohol-ether and water. of the base melting at 111-112 C. described in Example II.

EXAMPLE XIV 1 (p hydromyphenyl) 2 (a methyl phenyl-propylamino) -propan0l- (1 30 grams of l-(p-hydroxyphenyl) -2-aminopropanone-(l) of melting point 168-1'70 C. (containing 2 molecules of water of crystallization) were suspended in 130 ccs. pure methanol and. after addition of 27 grams of benzyl acetone and 0.5 grams of platinum oxide the whole was shaken in contact with hydrogen. After 6 to 8 hours rather more than 2 mols of hydrogen had been taken up; the hydrogenation then came practically to a standstill. The solution was worked up in the usual manner, for example, by concentrating in vacuo after acidification with hydrochloric acid and boiling the residue with 70 cos. of acetone and of the theoretical yield was obtained of a mixture of the hydrochloride of equal parts of the bases melting at Ill-112 C. and 139-140 C.

Ethanol can be used as the solvent, instead of methanol, with the same result, but the hydrogenation takes rather longer. Instead of 0.5 gram of platinum oxide, 10 grams of a 10% palladium hydroxide barium sulphate catalyst or 25 grams of Raney nickel can be used, and in this case hydrogenation is effected under raised pressure to accelerate the taking up of hydrogen.

. EXAMPLE XV Preparation of 1 (p hydroxyphenyl) 2 (amethyl-'y-phenyl-propylamino) -propanol- (1 30 grams of l-(p-hydroxyphenyl)-2-aminopropanone-(l) w re hydrogenated as described is obtained in It was identical with the hydrochloride 1 13. in Example XIII, but an-equal quantity of benzal acetonezwasxus'edxinsteadof 27-30 grams ofbenzy-l acetone. More than 3 mols of hydrogen were taken up. Working-up yielded a mixture of hydrochlorides, having a crude melting point of 210-211 C., the yield and the composition being thesame as in Example XIV;

EXAMPLE Preparation of 1 (p hydroxyphenyl) 2 phen'y'l-propylamino) -2Jropanol- 1) Bgrams 'ofr 1 (p hydroxyphen'yl)- 2-amino--- propanone-(l) (melting point 168 C. with-2 mols of water of crystallization) were shaken in'con tact with hydrogen in 37 cos. methanol with 2.5 grams of freshly distilled hydrosuccinaldehyde and 013 gram of platinum oxide; After about 2 hours hydrogen was no longer taken up. The solution was filtered from thecatalyst; the filtrate wasacidified with concentratedhydrochloric acid andevaporated to dryness in vacuo. The residue was triturated with acetone and gave the hydrochloride of the compound specified in the example heading of melting point 174-175" C. 80% aqueous methanol canbe used with the same success as anhydrous methanol.

EXAMPLE XVII 1-(p-hydmxyphenyl)'-2-(a methyZ phenylpropylamino) -butanol- (1 2 g. of. thehydr-ochloride of l-(p-benzylhydroxphenyl) 2. (a methyl v phenyl propylamino)'-butanol-(1) of melting point 202 C. in 50 cc. of'methanol'was shaken with l g. of 2% palladium-barium sulphate catalyst under hydrogen until no more hydrogen was taken up. The absorption of hydrogen corresponded to 1 mol: The filtrate'was concentrated in vacuo and the hydrochloride of the phenol base was obtained by precipitation with ether, which base after crystallization from methanol had a melting point of 200 C.

The initial material was. prepared in the following manner: l-p-benzylhydroxy butyrophenone was-brominated in known manner and reacted with l-phenyl-Ii-aminobutane to produce a stereoisomeric mixture of l-(p-benzylhydroxyphenyl) -2'-(a-methyl- 'y phenyl-propylamino) butanone; which was separated by fractional crystallization of the hydrochloride. By hydrogenation of the free base with platinum oxide (PtOz) in methanol the twostereoisomeric l-(pbenzylhydroxyphenyl) 2' (amethyl'y-phenyl propylamino) butanols- 1) were obtained.

EXAMPLE XVIII I l-(p-hydromyphenyl) 2 (a-methyl- -phenylprom/lamina) -butanol- (I) 10 g. of the hydrochloride of the stereoisomer l-(p benzylhydroxyphenyl) 2 (a. methyl-vplienylpropylamino) butanol (1') of melting. point 156 C: were hydrogenated as in Example I and g. of the hydrochloride of l-(p-hydroxyphenyl) -2-(a-methyl-' -phenyl propylamino) butanol-(l) were isolated. After re-crystallization from methanol the melting point was 200 C.

EXAMPLE XIX Z-(p-hydroxyphenyl)-2-(a-methyl ,6 phenylethylamz'no) -butanol- (1 18.1 g. of l-(p-hydroxyphenyl) -2-amino-lbutanol (Chemisches Centralblatt (1932), II, 91) was suspended in 50 cc. of methanol and 13.4 g. of phenyl acetone in 100 cc. of methanol were mixed presence of '0.2 g; of platinumioxide (PtO nZ under hydrogen until no more hydrogen was taken up". The absorption amounted to 1.05 mols; The'filtrate from the catalyst was freed from methanol invacuo. the radical dissolved'in ether, the undissolved' portion filtered off and the mixture of stereoisomeric hydrochlorides obtained by the addition of ethe'ric hydrogen chloride in a yield of 25 g. from which by fractional crystallization one of the. two stereoisomeric hydrochlorides was obtainedpure'with a melting point of'230 C.

EXAMPLE XX 1 (p hydroxyphenol) .2 phenyZ-propylamino) -butanol- (1) 18.1 g. of 1--(p-'hydroxyphenyl)-2-amino-1- butanol was suspended. in cc. of methanol and shakenwithoiag. of platinum oxide (PtOz) under hydrogen and'during' three-quarters of an hour a methanolicsolution of 13.4 g. of phenylpropionaldehydewasadded dropwlse; After oneand-a-half hours the absorption of hydrogen ceased; the absorption being 1.9 mole of hydrogen. The-filtrate from the catalyst was freed from the solvent in vacuo; the radical was taken up in ether and a well-crystallizing hydrochloride was obtained with etheric hydrogen chloride which after re-crystallization from absolute alcohol was obtained'in a yield of 19 g. and a melting point of 208 C.

EXAMPLE XXI I-(p hydroazyphenyl) 2 ('y phenyl butylamino) -butanol- (1) 15.5 g. of l-(p-hydroxyphenyl)-2-('yphenylbutylamino)-butanone of melting point 151 C. was dissolvedinl'l'O cc. of methanol at 50 C. and shaken with 2 g. of 2% palladium-barium'sulph-ate catalyst under hydrogen until no more hydrogen was taken up; The absorption ceased after 1.1 mols of hydrogen: had been absorbed. The. filtrate from the catalyst was brought to dryness in vacuo, the radical dissolved in ether, filtered from the undissolved portion and the hydrochloride of 1(p-hydroxyphenyl)'- 2 (yphenyl-butylamino)-butanol-(1) was obtained with etheric hydrogen chloride. in-a yield:'of.80% of the theoretical which, after R crystallization, had a'meltlng point of 192 C.

EXAMPLE XIXII Z-(p-hydroxyphenyl) 2' (w-methyl-s-phenylmethylamino butrmoZ- (1:)

14.2 g. of 1-(p-hydroxyphenyl) 2-(a-methyl-aphenyl-methylamino)"-butanone of melting. point 181-182 C. was'dissolved in cc. of methanol at 50 C'. and-shaken with-3 g. of a 2% palladiumbarium sulphate catalyst under hydrogen until no more hydrogen was takenup. The. absorption amounted to exactly 1v mol. The working. up was carried out as in Example XX; The hydro.- chloride of the desired compound was re-crystallized from aqueous alcohol and had a melting point of 209-210 C.

The initial material for Examples XXI and XXII is easily obtained by the reaction of pbenzylhydroxy-a-brom-butyro-phenone with lphenyll-amino-butane or with a-phenyl-ethylamine to form 1-(p-benzylhydroxyphenyl)-2-' phenyl-butylamino) -butanone (melting point of the hydrochloride about 193 C.) or to form 1- (p benzylhydroxyphenyl) 2 (a methyl-aphenyl methyl-amino)-butanone (melting point of the hydrochloride 240 C.) and their hydrogenolytic debenzylation with a palladium-barium sulphate catalyst.

We claim:

1. An aralkylamino alkane product of the group consisting of the acid addition salts and free base represented by the general formula for the base in which X is a member of the group of radicals consisting of CO- and CHOH-, in which R is a member of the group consisting of hydrogen and a phenyl methyl radical, in which P is a member'of the group consisting of phenyl and a methyl phenyl radical, and in which Y is an alkyl radical of from 1-2 C atoms.

2. The product in accordance with claim 1 in which the same is the free base, in which X is I 3. The product in accordance with claim 1 in which the same is an acid addition salt, in which X is the CO radical, in which R is hydrogen and in which P is the phenyl radical 4. An aralkylamino alkane base represented by the general formula 5. An aralkylamino alkane acid addition salt represented by the general formula for the base 6. The product in accordance with claim 5 in which said salt is the hydrochloride of said base. 7. The product in accordance with claim 5 in which said salt is the hydrobromide of said base. 8. In the production of an aralkylamino alkane product the improvement which comprises hydrogenating, in the presence of a Raney nickel catalyst, a member of the group consisting of the acid addition salt and free base of a ketone represented by the general formula (p) R'-0Hto-cHi-o OCHNHCH-CHrGHz-P Y CH3 in which R represents a phenyl radical, in which P is a member of the group consisting of phenyl and a methyl phenyl radical and in which Y is a member of the group consisting of methyl and ethyl radicals.

9. In the production of an aralkylamino alkane product the improvement which comprises hydrogenating, in the presence of a Raney nickel catalyst, the acid addition salt of a ketone represented by the general formula for the base in which R. represents a phenyl radical, in which P is a member of the group consisting of phenyl and a methyl phenyl radical and in which Y is a 16 member of the group consisting of methyl and ethyl radicals to thereby convert said group into a free OH group, and thereafter hyin which R represents a phenyl radical, in which P is a member of the group consisting of phenyl and a methyl phenyl radical, and in which Y is a member of the group consisting of methyl and ethyl radicals, to thereby convert said C0 group into a CHOH group and said O-CI-Iz-R.

group into a free OH group.

11. The improvement in accordance with claim 9 in which said hydrogenation is carried out using at least one mol equivalent of one member of the group consisting of alkali metalhydroxide and alkali metal alcoholate.

12 In the production of an aralkylamino alkane product the improvement which comprises hydrogenating in the presence of a hydrogenation catalyst a suspension of l-(p-hydroxyphenyl)2-amino-propanone-(1) in an organic solvent, in which said propanone is but limitedly soluble, in the presence of 4-phenyl-butanone- (2).

13. Improvement in accordance with claim 12 in which said organic solvent is methanol.

14. Improvement in accordance with claim 12 in which said catalyst comprises platinum oxide.

15. Improvement in accordance with claim 14' in which said organic solvent is methanol.

IDA KULZ. ANNEMARIE' KiiLz, WALBURGA KiiLz, FRIEDRICH LEHMANN. Administrators of the estate of Fritz K1212,

deceased.

CLEMENS SCHOPF.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,061,136 Bockmuhl Nov. 17, 1936 FOREIGN PATENTS Number Country Date 669,574 Great Britain Apr. 2, 1952 968,273 France Apr. 12, 1950 1,001,547 France Oct. 24, 1951 

1. AN ARALKYLAMINO ALKANE PRODUCT OF THE GROUP CONSISTING OF THE ACID ADDITION SALTS AND FREE BASE REPRESENTED BY THE GENERAL FORMULA FOR THE BASE 